Complement proteins C5 and C3 are therapeutic targets for treatment of a variety of human diseases, disorders and conditions that are associated with complement activation, for example, ocular inflammatory and retinal degenerative diseases. The evaluation of pharmacokinetics (PK) and pharmacodynamics (PD) of therapeutic molecules that specifically target human C5 or human C3 proteins are routinely performed in non-human animals, e.g., rodents, e.g., mice or rats. However, the PD of such therapeutic molecules cannot properly be determined in certain non-human animals because these therapeutic molecules do not target the endogenous C5 or C3 proteins.
Moreover, the evaluation of therapeutic efficacy of human-specific C5 or C3 protein antagonists various non-human animal models of diseases associated with an activated complement system is problematic in non-human animals in which such species-specific antagonists do not interact with the endogenous C5 or C3 proteins.
Accordingly, there is a need for non-human animals, e.g., rodents, e.g., murine animals, e.g., mice or rats, in which the C5 and/or C3 genes of the non-human animal are humanized in whole or in part or replaced (e.g., at the endogenous non-human loci) with human C5 and/or C3 genes comprising sequences encoding human or humanized C5 and/or C3 proteins, respectively. There is a need for such humanized non-human animals that express human or humanized C5 and/or C3 proteins in serum at concentrations similar to that of C5 and/or C3 proteins, respectively, present in serum of an age-matched non-human animal, that expresses functional C5 and/or C3 proteins, but does not comprise the human or humanized C5 and/or C3 genes, respectively.
Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles, electronic database entries, etc.) are referenced. The disclosure of all patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety for all purposes.